PROJECT SUMMARY/ABSTRACT Colorectal cancers (CRC) are the second leading cause of cancer mortality in the United States. Management of CRC patients includes the need to accurately ascertain patient prognosis and to detect progression following therapy. We hypothesize that Tumor Infiltrating Lymphocyte (TIL) count and clonality will be able to more accurately predict patient outcome than currently existing approaches that are based on using disease stage only. We also hypothesize that measuring the TIL clones in T cells derived from blood following therapy will provide a method to accurately predict progression of CRC. Our hypothesis is supported by growing evidence that the presence of intraepithelial Tumor Infiltrating Lymphocytes (TILs) is strongly related to patient outcome in CRCs and many other diseases. Our opportunity to succeed is based on new technologies developed by our team. While current technologies for assessing TILs are not appropriate for use in a clinical setting, we will use new technologies developed by our team that can reproducibly and quantitatively measure the overall number and clonality of TILs in a specific sample. The assay Immunoseq quantifies rearranged T-cell receptor CDR3 chains. We will combine these measures with additional factors to derive a prognostic metric that can be practically used in a clinical setting. To derive our metric we will measure colon cancer biopsy sections and matched blood samples collected at two time points (baseline and 6 months) from 80 stage II and III colon cancer patients with at least two years of clinical follow-up.